Phosphate levels are regulated predominantly by the kidneys and in healthy people phosphate homeostasis is maintained by urinary excretion. Phosphate concentrations in serum can increase dramatically in patients with chronic renal failure and lead to secondary hyperthyroidism and soft tissue calcification. This calcification results in atherosclerosis of the coronary arteries and premature heart disease, which is the major cause of death in end-stage renal disease (ESRD). Dietary phosphate restriction alone is usually insufficient to control hyperphosphatemia in haemodialysis patients and the oral intake of phosphate binders is required to reduce intestinal absorption.
Aluminium and calcium compounds have been widely used to bind dietary phosphate, but there are concerns regarding their long-term safety. The use of aluminium-based phosphate binders results in tissue accumulation of this element and may result in systemic toxicity. The administration of large quantities of calcium-based phosphate binders can result in hypercalcemia and subsequently aggravate tissue calcification.
Sevelamer (polyallylamine hydrochloride), a synthetic polymer commercialised under the name of Renagel, is an anion exchange resin used to bind dietary phosphate. However, the binding action of this resin is not specific to phosphate and large doses have to be administered to control serum phosphate in ESRD patients, which can lead to low patient compliance. Lanthanum carbonate is an approved phosphate binder commercialised under the name of Fosrenol. However, concerns exist about the long-term accumulation and toxicity of lanthanum in tissues.
U.S. Pat. No. 6,903,235 describes the use of ferric citrate, a soluble iron compound, to bind dietary phosphate. However, the long-term use of a soluble iron compound is likely to lead to gastrointestinal side-effects due to the redox activity of free iron in the gut lumen, which may subsequently result in low compliance.
WO 2007/088343 describes a phosphate binder formed from the reaction of aqueous solutions of magnesium sulphate and ferric sulphate in the presence of sodium hydroxide and sodium carbonate, probably leading to an iron magnesium hydroxy carbonate with an hydrotalcitic structure. This phosphate binder is known as “Alpharen”, but suffers from the disadvantage that it binds relatively small amounts of phosphate and moreover releases Mg2+ in the stomach, leading to frequent side-effects.
The ability to bind phosphate by iron oxo-hydroxides is known in the art. For example, U.S. Pat. No. 6,174,442 describes an adsorbent for phosphate using β-iron hydroxide stabilized by carbohydrates and/or humic acid. However, its binding ability is limited and the manufacturing process is unsuitable for the preparation of large quantities of material. WO 2008/071747 describes an adsorbent for phosphate containing γ-iron oxide-hydroxide stabilized by insoluble and soluble carbohydrates. However, the phosphate binding activity of the materials described therein is limited to very low pH, limiting its effectiveness as a phosphate binder.
In summary, there is no ideal phosphate binder in current use and existing materials have one or many flaws, most commonly toxicity or accumulation, cost, efficacy of phosphate removal, acidosis and/or patient intolerance.
Accordingly, there remains a continuing need in the art to develop further phosphate binders that overcome or ameliorate some of the drawbacks of existing treatments.